Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques.

BACKGROUND: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. NEW METHOD: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125I-labeled DNSP-11 dose. RESULTS: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. COMPARISON WITH EXISTING METHODS: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. CONCLUSIONS: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

The use of the harmonic scalpel in thyroidectomy: 'beyond the learning curve'.

INTRODUCTION: Safe and effective haemostasis in surgery is clearly essential, and in the neck where risks of airway compromise are also present any new technology that purports to offer advantages must be rigorously evaluated. We describe our experience with the use of the Harmonic Scalpel [Ethicon UK] in thyroidectomy. PATIENTS AND METHODS: A retrospective clinical review of 183 patients undergoing hemi or total thyroidectomies from 12 months prior to using the harmonic scalpel (2003; n = 77) and 12 months 'beyond the learning curve' (2006; n = 106). RESULTS: The results demonstrate that, once past the learning curve, the use of the harmonic scalpel during thyroidectomy significantly reduces operative time and postoperative hypocalcaemia, and is as safe as conventional surgery with regard to voice change and bleeding. CONCLUSIONS: The harmonic scalpel is as safe as conventional methods of haemostasis and operations using this technique are quicker once the need to have repetitive 'clip, cut and tie' routines is avoided.

Different patterns of relapse associated with three intensive treatment regimens for pediatric E-rosette positive T-cell leukemia: a Pediatric Oncology Group study.

One hundred and ninety-three children with T-cell acute lymphocytic leukemia (T-ALL) whose leukemia cells were E-rosette positive were treated on a Pediatric Oncology Group study (1979-1986) designed specifically for patients with T-ALL. The results of modified LSA2L2 therapy with or without intensified intrathecal chemotherapy and cranial irradiation (radiotherapy) were compared with those obtained using a simpler multi-agent protocol which included radiotherapy (T-cell 2). The complete remission (approximately 90%) and 3-year event-free survival rates (approximately 40%) were similar in the three treatment groups. However, the pattern of extramedullary relapse varied according to specific treatment regimen. Patients who received LSA2L2 therapy with less intensive intrathecal chemotherapy and no radiotherapy had a central nervous system (CNS) relapse rate (i.e. isolated CNS +/- other site) of over 20%, compared to only 10% for patients receiving the same systemic chemotherapy with intensified intrathecal therapy and radiotherapy, and less than 5% for those receiving T-cell 2 therapy. In contrast, males receiving T-cell 2 therapy had a testicular relapse rate of greater than 20% compared to less than 10% for patients receiving either regimen (i.e. +/- intensified intrathecal chemotherapy and radiotherapy) of modified LSA2L2 therapy. We conclude that, in the context of these therapies, central nervous system irradiation plus intensive triple (hydrocortisone, methotrexate, cytarabine) intrathecal chemotherapy is more effective than CNS preventative therapy comprised of intrathecal low-dose methotrexate only, and that the more complex multi-agent chemotherapy used in the modified LSA2L2 regimens appeared to be more effective in prevention of testicular leukemia, indicating that the effectiveness of sanctuary site treatment was therapy-specific.

An NMR study of lithium responding manic depressive patients.

Manic depressive patients on long-term prophylactic therapy with lithium carbonate are examined by nuclear magnetic resonance imaging of the brain. Their ventricular brain ratios and cerebral grey and white matter spin lattice relaxation times (T1) are within normal limits. The implication of these findings in the light of previous studies using other techniques is discussed.

A validity study of a new rating scale for psychiatric patients.

A criterion validation of a new scale, REHAB (Rehabilitation Evaluation Hall And Baker) (1) is described. Forty-three long-stay psychiatric patients from two wards were observed by a psychologist over a 2-week period using a time sampling procedure. The observed behaviour was coded into predetermined categories based on Blunden & Kushlick's (2) concept of engagement. Also during this period the ward nurses rated the 43 patients using the REHAB assessment. The time sampled observations were correlated with REHAB factors and items. Five hypotheses about the relationship between the two measures were tested. Four of the five hypotheses were supported by the data. Overall, despite certain limitations of the study, it is concluded that evidence is provided for the criterion validity of REHAB.

Computerized tomography scan findings in children with acute lymphocytic leukemia treated with three different methods of central nervous system prophylaxis.

Computerized tomography (CT) scans of the head were done on 93 children with acute lymphocytic leukemia in continuous complete remission who had been randomly assigned to three different methods. of central nervous system (CNS) prophylaxis. Twenty-nine children had received six doses of intrathecal methotrexate, 30 had received six doses of intrathecal methotrexate plus 2400 rad of cranial irradiation, and 34 had received six doses of intrathecal methotrexate plus three courses of intermediate-dose intravenous methotrexate. The overall incidence of abnormal scans was 35%, of which 91% were felt to represent minimal abnormalities. CT scan abnormalities were noted in 30% of the children receiving intrathecal methotrexate only, in 40% of those receiving intrathecal methotrexate plus cranial irradiation, and in 35% of those receiving intrathecal methotrexate plus intermediate dose methotrexate. These differences were not statistically significant. None of the three methods of CNS prophylaxis resulted in significant CT scan abnormalities. However, the few moderately or markedly abnormal scans evaluated were restricted to patients who received intrathecal methotrexate plus cranial irradiation. The clinical significance of CT scan abnormalities in leukemic children receiving these treatments remains unclear.

Nuclear magnetic resonance (NMR). II. Imaging in dementia.

Proton NMR imaging of the brain is rapidly becoming established as a useful investigative tool in medicine. This paper examines the usefulness of the NMR parameters--spin-lattice relaxation time (T1) and proton density (PD)--in differentiating groups of patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID) from each other, and from elderly controls. T1 values increase with severity of dementia. NMR parameters may also be of use in localising regions of brain damage.

[NMR imaging in dementia states. A diagnostic and quantitative study]. / NMR-imaging in Demenzzuständen. Eine diagnostische und quantitative studie.

Spin lattic relaxation times (T1) and proton density derived from proton nuclear magnetic resonance imaging data are measured in elderly patients with senile dementia of Alzheimer type (SDAT) and multi infarct dementia (MID) and the results compared with elderly controls. T1 values of the cerebral white matter are increased in the dementia groups and there is a statistical correlation with severity. Patients with SDAT have significantly differing proton density measures in cerebral white matter from those with MID. The potential value of these results are discussed together with the possible application to identify regional areas of damage.

Cognitive evaluation following NMR imaging of the brain.

Nuclear magnetic resonance imaging of the brain will soon be a standard neuroradiological investigation. Previous work has indicated that this is a safe procedure. Tests which measure various aspects of cognition were performed on volunteer subjects before and after (medium and short term) NMR brain imaging and indicate that deterioration did not occur.

Mea culpa? A study of the relationships among personality traits, life-events and ascribed accident causation.

On the basis of their own reports, accident victims attending a casualty department were independently assigned either to a causal group (n = 25), i.e. apparently culpable in causing their accident, or a non-causal group (n = 25). Comparisons were made between these two groups of patients on: (1) sociodemographic characteristics; (2) locus of control; (3) recent life-events; and (4) cognitive failures. The groups differed only in their tendency to perceive locus of control as being internal (causal group) or external (non-causal group).